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Nutritional support in early Alzheimer’s disease: what, why and when?

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Presentation on theme: "Nutritional support in early Alzheimer’s disease: what, why and when?"— Presentation transcript:

1 Nutritional support in early Alzheimer’s disease: what, why and when?
Laus Broersen, PhD Senior Neuroscientist Nutricia Research, Advanced Medical Nutrition Utrecht, The Netherlands

2 AD specific nutritional needs for membrane and synapse formation
Lower nutrient intake, uptake and metabolism Lower brain nutrient levels AD-induced compromised nutrient availability 1 A Lower blood nutrient levels B C Patients with AD show lower number of brain synapses In AD a specific need exists to enhance synapse formation Patients with AD show lower level of neuronal membranes 2 A B Membrane and synapse formation dependent on nutrient availability C AD specific nutrient requirement to meet the increased demand for synapse formation 3 Souvenaid addresses the nutritional need to support increased synapse formation in patients with AD 4

3 Synapse loss is structural basis of functional deficits in AD
Reduced number of synapses Control MCI AD 5 10 * -13% -44% # synapses dentate gyrus (x1010) Synapse loss in AD is confirmed in >30 publications

4 Loss of dendritic spines in AD
Control AD Control AD Control AD Control AD Catala et al (1988) Hum Neurobiol Einstein et al (1994) J Neurosci Mavroudis et al (2010) Am J Alz Dis oth Dement Tsamis et al (2010) Curr Alzheim Res

5 Decreased brain phospholipids in AD indicates disrupted membrane integrity
Conclusion: Phospholipids provide an optimal membrane environment for protein interactions, trafficking and function. There is increasing evidence that phospholipid changes occur during pathogenic processes in Alzheimer’s disease. Kosicek, M. and S. Hecimovic (2013). "Phospholipids and Alzheimer's disease: alterations, mechanisms and potential biomarkers." Int J Mol Sci 14(1): Brain is one of the richest organs in lipid content. Phospholipids (glycerophospholipids and sphingolipids) are important building blocks of cell membranes, which provide an optimal environment for protein interactions, trafficking and function. Because of that, alterations in their cellular levels could lead to different pathogenic processes in the brain, such as in Alzheimer's disease (AD), the most common type of dementia among older populations. There is increasing evidence that phospholipid changes occur during pathogenic processes in AD. It is known that lipids are tightly connected with metabolism of the Amyloid Precursor Protein (APP), which produces Amyloid-beta peptide (Abeta), the main component of senile plaques, which represent the main pathological hallmark of AD. However, the mechanism(s) of the lipid-effect on Abeta metabolism and AD pathogenesis is still not completely understood. This review summarizes the current knowledge on phospholipid changes occurring during normal aging and discusses phospholipid changes in the human brain associated with different stages of AD, as well changes in the cerebrospinal fluid and blood/plasma, which are interesting potential biomarkers for AD diagnosis and disease monitoring. At the end, we have discussed future perspectives of phospholipid changes as potential biomarkers and as targets for development of novel treatment strategies against AD. 4. Conclusions “… Phospholipids provide an optimal membrane environment for protein interactions, trafficking and function. There is increasing evidence that phospholipid changes occur during pathogenic processes in Alzheimer’s disease. …”

6 Dietary precursor control of neural membrane synthesis
The Kennedy pathway for biosynthesis of neuronal membrane Membranes are main constituents of synapses Phosphocholine CDP-choline Phosphatidylcholine New neuronal membrane Phospholipids Choline Uridine Omega-3 fatty acids Axon neurite dendritic spine Neurite Dendritic terminal As we know, the brain is not static: synaptic plasticity takes place. And for that, the brain needs synaptic membranes to be synthesized constantly. For this, the brain uses a pathway shown on the left, that is called the Kennedy pathway. This pathway uses nutrients, dietary precursors, to make more membrane. Importantly, this system is controled by low affinity enzymes, which means that by providing more precursors you get more endproduct: more synaptic membranes. In addition, it means that you need a specific combination of nutrients for optimal membrane synthesis, and not single nutrients.

7 Dietary precursor control of neural membrane synthesis
The Kennedy pathway for biosynthesis neuronal membrane Phosphocholine CDP-choline Phosphatidylcholine New neuronal membrane Phospholipids Choline Uridine Omega-3 fatty acids Coming back to the Kennedy pathway, it is long known that giving more of the nutrient choline will increase phosphocholine in the brain, However, giving only choline will produce a lot more membrane because of other rate-limiting steps, such as the one requiring the nucleotide uridine to make more CDP-choline. Finaly, for going from CDP-choline to phospatidylcholine, you need specific polyunsaturated fatty acids, such as DHA, found in fish oil. Kennedy & Weiss (1956) J Biol Chem

8 Dietary precursors can be rate-limiting: Synergy between dietary precursors
Brain phospholipids (PE) (nmol/mg protein) UMP DHA *** * 20 40 60 80 100 120 So you need precursors to increase the synthesis of membranes. But, importantly, you need to give them all; otherwise one may become rate-limiting. Indeed, in a series of experiments performed at MIT, the three precursors, Uridine, DHA, and Choline, were shown to act in synergy to increase brain phospholipids. Example: feeding animals with only uridine or DHA will give a small increase in brain PLs, but combined feeding gives a much bigger increase: a classical example of synergy. The nutrients work together as an orchestra. Next question: will increased membrane synthesis also lead to more membrane-dependent structures: e.g. Neurites and dendritic spines Control Wurtman et al (2005, 2006) Brain Res

9 Dietary precursors increase membrane dominant structures: Dendritic spines
Spine Density hippocampus (for 50µM) Control (choline) UMP UMP DHA DHA ** * 20 40 60 80 100 Next it was shown that this also holds true for dendritic spines measured in vivo in the hippocampus. Again it was found that especially the combination of precursors increased dendritic spine density. Sakamoto et al (2007) Brain Res

10 B-vitamins: cofactors for endogenous production of membrane precursors
In order to stimulate membrane synthesis optimally, you not only need the precursors, but you also need so-called dietary cofactors, like B-vitamins. B-vitamins 6, 12 and folic acid are crucial in the PEMT-pathway in the liver. By improving methylation-status, the B-vits help to increase the availability of Choline and DHA. PEMT = phosphatidylethanolamine-N-methyltransferase

11 Precursor availability: B-vitamins increase plasma choline and DHA
B vitamins increase choline B vitamins dose-dependently increase DHA In separate experiments Van Wijk et al showed that supplementation of the 3 B-vitamins increased plasma choline and plasma DHA levels. Do note that these diets did not contain DHA! van Wijk et al (2011) Br J Nutr van Wijk et al (2012) Nutr Metabol

12 Nutritional precursors and cofactors: enhanced availability by Fortasyn Connect
Synapses are continuously being remodeled Synapses are part of the neuronal membrane Membranes consist of phospholipids Phospholipid synthesis depends on the presence of uridine, choline and DHA B-vitamins enhance precursor bioavailability Antioxidants protect the neuronal membrane and maintain its integrity, stability and function

13 Precursors and cofactors enhance synapse formation and function – basic science data
Confirmed & Published Fortasyn Connect Nutrient combinations Key phenomena being studied Increase precursor supply Co-factors increase precursor availability Increase phosphatide / membrane synthesis Improved membrane composition Increase neurite outgrowth Increase connectivity (grey and white matter integrity) Increase synaptic proteins Increase synaptic contacts Increase neurotransmission (ACh synthesis, release, receptors) Synergy between nutrients Reduced abeta production/plaque formation/toxicity Reduced neurodegeneration (immunoreactivty & NAA) Improve learning & memory / behavior 19-22 24 25 21,26 24,26,28 19,23 19,21,28 19,22,23,29 19,22,23 19,22,29-31 27 18 1,2 2,5,8,11,17 11,23 6,7 8 5,7,8,17 2,5,7,8 3,4 2,6,9,10 11,13-17 11,12 Cansev (2005) Brain Res Sakamoto (2007) Brain Res de Wilde (2002) Brain Res Jansen (2013) PLOS ONE Jansen (2013) Brain Struc Fun Ulus (2006) Cell Mol Neurobiol Farkas (2002) Brain Res de Bruin (2003) J Learn Mem Broersen (2013) J Alz Dis Koivisto (2013) in press Van Wijk (2011) Br J Nutr Wang (2007) Brain Res Holguin (2008) BehavBrainRes Savelkoul (2012) AAIC Wiesmann (2013) JAD Van Wijk (2012) Nutr Metab Kariv-Inbal (2012) JAD van Wijk (2014) JAD Zerbi (2013) Neurobiol Aging Wurtman (2006) Brain Res Grimm (2011) JBC de Wilde (2011) J Alz Dis Savelkoul (2011) ADPD Wang (2005) J Mol Neurosci Teather (2003) PNBP Cansev (2012) data on file Verheijen (2012) data on file Pooler (2005) Neuroscience de Wilde (2003) Brain Res Cansev (2013) data on file Savelkoul (2012) J Neurochem

14 AD risk and nutrient intake
Observational studies suggest a link between Mediterranean diet & AD risk, but data not fully consistent Mediterranean diet: High vegetables, legumes, fruits, and cereals High unsaturated fatty acids Low saturated fatty acids Moderately high fish Low-to-moderate dairy Low meat and poultry Regular but moderate amount of ethanol, primarily in the form of wine and generally, during meals AD incidence by diet tertile Some studies show an effect on MMSE and cognitive decline, others do not Psaltopoulou et al, 2008: No difference in MMSE after 6-13 years Better MMSE but not on other domains after 5 years No difference in 4-year cognitive change Tangney et al, 2011: Less cognitive decline over 7 years with high Mediterranean diet adherence Scarmeas et al (2006) Ann Neurol Scarmeas et al, Ann Neurol, 2006; Psaltopoulou et al, Public Health Nutr, 2008; Feart et al, JAMA, 2009; Cherbuin et al, Am J Geriatr Psychiatry, 2011; Tangney et al, Am J Clin Nutr, 2011

15 Systematic review and meta-analysis on nutrient availability in AD
According to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines Analyses by independent statisticians 15-30% lower all together Same found e.g. for vitamin E and C DHA insufficient studies to do meta-analysis 3 out of 4 reported lower levels in AD

16 Lopes da Silva (2013) Alz Dement
Systematic review and meta-analysis of literature: Lower plasma levels of precursors & cofactors in AD % Cognitive Intact elderly Plasma nutrient status in AD Meta-analyses, systematic review and observations 50 80 70 60 90 10 studies DHA EPA * Meta-analyses Lin (2012) JCP 6 studies 9 studies Vit B6 Choline data on file *** 37 studies 31 studies 20 studies 8 studies Folate Vit B12 Vit C Vit E Lopes da Silva (2013) Alz Dement 11 studies Selenium Systematic review Loef (2011) JAD 2 studies Uridine *1 *2 1:Trushina (2013) PLOS 2:Olde Rikkert (2013)ADPD The results of the meta-analyses for the whole set of papers (Left graph) and for the set of papers reporting no difference in protein/energy nourishment (Right graph) are presented as percentage of their respective elderly control groups. The dotted line in these figures represents the 100% value as observed in the control groups for the different nutrients. As can be observed from these figures the levels of the different nutrients in patients with AD are all below those of the control subjects (Left graph) even when only studies were selected that reported that protein/energy nourishment was unaffected (Right graph).

17 Epidemiological relate dietary patterns with AD risk
Lower nutrient status preceding classic protein energy malnutrition Epidemiological relate dietary patterns with AD risk Next slides I give a brief summary regarding the scientific data and arguments we have to address the requirements for FSMP and medical foods This is the model that we use to define AD specific nutrietn requirements As you will see in a minute the starting point re nutrient availability is lower in AD compard with age matched controls We hypothesise that there are 3 phenomena that contribute to these lower levels and together accumulated in a distinct increased need Nutrietn intake is well know to alter in some AD pateints, both qualitatively and quantitatively There’s changes in nutrietn handling, changes in metabolism and uptake, will give example for this Nutrietns needed to compensate for synaptic loss might be higher Mi et al (2013) Nutrition

18 Development of Souvenaid: addressing AD specific requirements
Stimulating synapse formation requires specific nutrients Development of Souvenaid: addressing AD specific requirements Lower Nutrient status & altered nutrient metabolism Increased nutritional need cannot be met by the regular diet 400 mg Choline 300 mg EPA 625 mg UMP 3 mcg Vit B12 1 mg Vit B6 80 mg Vit C 1200 mg DHA 400 mcg Folate 106 mg Phospholipids 60 mcg Selenium 40 mg Vit E Uridine (UMP), Omega-3 fatty acids, Phosholipids & Choline, B-Vitamins, Antioxidants HYPOTHESIS: Souvenaid successfully addresses an unmet nutritional need in people with AD by increasing their intake of these dietary precursors and co-factors

19 MMSE 14-24, stable on AD drugs
Souvenaid Clinical Development Prodromal AD Mild AD Moderate AD S-Connect ADAS-cog MMSE 14-24, stable on AD drugs Souvenir I WMS-r & ADAS-cog MMSE 20-26, drug-naïve Souvenir II NTB + EEG MMSE ≥ 20, drug-naïve Open Label Open Label Extension Study Safety + Compliance + NTB MEG study MEG + EEG +NTB MMSE ≥ 20, drug-naïve MRS study 31P and 1H-MRS MMSE ≥ 20, drug-naïve NL-Enigma 18FDG-PET MMSE ≥ 20, drug-naïve LipiDiDiet NTB + MRI / CSF MMSE ≥ 24, drug-naïve Souvenir I received funding from NL STW Souvenir II receives funding from the NL Food & Nutrition Delta project, FND N°10003 LipiDiDiet is funded by the EU FP7 project LipiDiDiet, Grant Agreement N° NL-Enigma funded by NWO NIHC project, N°

20 S-Connect study: mild to moderate AD on AD medication
Principle investigators: David Bennett and Raj Shah, Rush, Chicago Multi-centre (48 sites in the US), randomized, controlled trial Intervention 24 weeks Primary outcome: ADAS-cog-11 No significant effect (p=0.513) during 24 weeks ITT, MMRM, data are mean ±SE Baseline Characteristics Control (n = 262) Active (n = 265) Age (y) 76.9 (8.2) 76.6 (8.2) Sex: males (n[%]) 127 (48.5%) 126 (47.5%) Years of education on top of primary school 6.4 (3.5) 6.7 (3.6) Total MMSE score 19.3 (3.0) 19.5 (3.2) Duration AD since diagnosis  (months) 34.9 (29.6) 32.7 (25.0) Acetylcholinesterase inhibitors 243 (92.7%) 251 (94.7%) NMDA antagonist 170 (64.9%) 177 (66.8%) BMI (kg/m2) 26.64 (4.56) 26.19 (4.51) t≤-3 t= wks n=527 Souvenaid (n=265) Control (n=262) Outcome parameters Next we conducted the S-connect trial in mild to moderate AD on AD medication. Unfortunately, Souvenaid did not improve ADAS-cog when given on top of AD medication. Values are mean ±SD, unless stated otherwise Shah et al (2013) Alz Res Ther

21 Souvenir I: Proof of concept study in drug-naive mild AD
Multi-country (NL, Bel, Ger, UK, US), randomized, controlled trial Intervention 12 weeks (+ optional 12 wk extension) Co-primary outcomes: WMS-r delayed verbal recall ADAS-cog-13 Significantly more responders after 12 weeks (p=0.021) Change in WMS-r delayed verbal recall score Baseline characteristics Control (n = 106) Souvenaid Sex (male/female; counts) 52 / 54 54 / 52 Age (y) 73.3 ± 7.8 74.1 ± 7.2 BMI (kg/m2) 26.2 ± 3.5 26.2 ± 4.8 Years of education on top of primary school 6.0 ± 4.0 5.5 ± 3.9 Days since AD diagnosis (median) 31.5 (0–1036) 30.0 (0–1932) Total MMSE score 24.0 ± 2.5 23.8 ± 2.7 t≤-3 t= wks n=212 Souvenaid (n=106) Control (n=106) Outcome parameters In our first clinical trial (Souvenir 1, PI=Philip Scheltens) we studied Souvenaid and control in drug-naïve mild AD, and found an improvement of memory as measured by the co-primary endpoint, the Wechsler Memory Scale revised after 12 weeks Values are mean ±SD, unless stated otherwise Scheltens et al (2010) Alzh Dement

22 Souvenir II study: drug-naive mild AD
Multi-country (NL, Ger, Bel, Fr, It, Sp), randomized, controlled trial Intervention 24 weeks Primary outcome: Memory Domain NTB (z-score): RAVLT immediate, delayed, recognition and VPA immediate and delayed Significantly improved memory (p=0.023) Memory domain score (z-score) of NTB Baseline characteristics Control (n = 129) Souvenaid (n = 130) Age (y) 73.2 (8.4) 74.4 (6.9) Sex: males (n[%]) 64 (49.6) 68 (52.3) Years of education on top of primary school 6.6 (4.6) 6.5 (4.8) Total MMSE score 25.1 (2.9) 25.1 (2.8) Duration AD since diagnosis (months) (median[range]) 2.0 ( ) 1.0 ( ) BMI (kg/m2) 26.7 (4.2) 26.1 (4.1) t≤-3 t= wks n=259 Souvenaid (n=130) Control (n=129) Outcome parameters We continued with the Souvenir 2 study, to get confirmation of our findings in mild AD. Now this study continued for 24 weeks, and again it was found that patients on the Active improved memory performance as compared to Control! In this study population, we did 2 additional substudies of which I would like to share the first data with you: we first looked with EEG to see whether we could obtain indications for improved functional brain connectivity in our patients, And also performed an open label extension study in which both groups now continued on Souvenaid. Values are mean ±SD, unless stated otherwise Scheltens et al (2012) J Alzheimers Dis

23 Electrical activity at the synapse – EEG biomarker for functional connectivity
Signal strength Peak Frequency PLI Functional connectivity Phase Lag Index (PLI) Healthy AD Network Organization Clustering / Path length van Straaten en Stam (Amsterdam) looked at various EEG measures that are known to be affected in AD: signal strength, functional connectivity and network organization. Interestingly, several of these measures showed deterioration over the course of the 24 week study, but more importantly, Souvenaid was able to improve all measures. These data indicate that in AD patients on Souvenaid similar effects on brain connectivity may occur as previously observed in animals on Fortasyn diet. P=0.019 P=0.011 P=0.009 Scheltens et al (2012) J Alzheimers Dis; de Waal et al (2014) PlosOne

24 Changes may reflect the breakdown of neuronal membranes
Mapstone et al. identified a biomarker panel of 10 plasma lipids that can predict conversion from cognitive healthy to MCI/AD within 2–3 years with >90% accuracy Changes may reflect the breakdown of neuronal membranes Highly publicitized findings set of 10 plasma lipids, including 8 phospholipids levels are lower in converters and MCI/AD subjects

25 Souvenaid increases levels of the biomarker phospholipids
Baseline and 24-week plasma samples from the Souvenir II study Drug-naïve patients with very mild AD Polar lipid profile 5 / 7 measured phospholipids reported by Mapstone significantly increased by Souvenaid By providing nutrients which normally rate-limit phospholipid synthesis Souvenaid can: modify a biomarker profile reflecting disturbed phospholipid metabolism be useful in asymptomatic subjects with plasma lipid biomarker profiles predictive for conversion to AD * P<0.001; Souvenaid vs. Control using ANCOVA

26 MMSE 14-24, stable on AD drugs
Souvenaid Clinical Development Prodromal AD Mild AD Moderate AD S-Connect ADAS-cog MMSE 14-24, stable on AD drugs Souvenir I WMS-r & ADAS-cog MMSE 20-26, drug-naïve Souvenir II NTB + EEG MMSE ≥ 20, drug-naïve Open Label Open Label Extension Study Safety + Compliance + NTB MEG study MEG + EEG +NTB MMSE ≥ 20, drug-naïve MRS study 31P and 1H-MRS MMSE ≥ 20, drug-naïve NL-Enigma 18FDG-PET MMSE ≥ 20, drug-naïve LipiDiDiet NTB + MRI / CSF MMSE ≥ 24, drug-naïve Souvenir I received funding from NL STW Souvenir II receives funding from the NL Food & Nutrition Delta project, FND N°10003 LipiDiDiet is funded by the EU FP7 project LipiDiDiet, Grant Agreement N° NL-Enigma funded by NWO NIHC project, N°

27 Thank you!


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